Upregulation of Ih expressed in IB4-negative Aδ nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain

Abstract

Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4− Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4- Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy.

Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current (Ih) in large-diameter dorsal root ganglion neurons

“…This is inconsistent with our previous report in IB4 − Aδ neurons where CRP condition produces obvious shift of V 0.5 of I h in depolarizing direction. 4 This discrepancy might be due to different changes in kinetics of HCN channels responsible for I h in different subgroups of DRG neurons under CRP states. Taken together, chronic compression of cervical DRGs produced obvious upregulation of I h in large DRG neurons, this extends our previous report in nociceptive IB4 − Aδ DRG neurons under CRP condition.…”

“…Taken together, chronic compression of cervical DRGs produced obvious upregulation of I h in large DRG neurons, this extends our previous report in nociceptive IB4 − Aδ DRG neurons under CRP condition. 4 …”

Neurostimulation for Refractory Cervicogenic Headache: A Three-Year Retrospective Study

“…The treating physician later estimated the frequency regularly during patient follow-ups. The patients demonstrated sensory abnormalities on the clinical examination of the sensory territories of C2 and/or C3 including brush allodynia (15), Von Frey filaments testing (16), pressure algometer (17), and hypoesthesia to touch and pinprick testing (18). Patients also showed tenderness to paraspinal, supraorbital, and/or jaw skin roll technique (19).…”

Characterization of Different Types of Excitability in Large Somatosensory Neurons and Its Plastic Changes in Pathological Pain States

“…Several ionic currents have been implicated in the membrane excitability and repetitive firing in neurons including I NaP , I h [ 15 , 38 , 39 , 40 ]. Previous studies in mesencephalic V neurons have reported a crucial role of I Na,P in the determination of excitability type [ 13 ].…”